title: Small molecule agonists of the orphan nuclear receptors steroidogenic factor-1 (SF-1, NR5A1) and liver receptor homologue-1 (LRH-1, NR5A2).
abstract: The crystal structure of LRH-1 ligand binding domain bound to our previously reported agonist 3-(E-oct-4-en-4-yl)-1-phenylamino-2-phenyl-cis-bicyclo[3.3.0]oct-2-ene 5 is described. Two new classes of agonists in which the bridgehead anilino group from our first series was replaced with an alkoxy or 1-ethenyl group were designed, synthesized, and tested for activity in a peptide recruitment assay. Both new classes gave very active compounds, particularly against SF-1. Structure-activity studies led to excellent dual-LRH-1/SF-1 agonists (e.g., RJW100) as well as compounds selective for LRH-1 (RJW101) and SF-1 (RJW102 and RJW103). The series based on 1-ethenyl substitution was acid stable, overcoming a significant drawback of our original bridgehead anilino-substituted series. Initial studies on the regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes.
authors.affiliation: School of Chemistry, University of Southampton, Southampton, Hants, SO17 1BJ, United Kingdom. rjw1@soton.ac.uk
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Whitby
authors.forename: Jozef
authors.initials: J
authors.lastname: Stec
authors.forename: Raymond D
authors.initials: RD
authors.lastname: Blind
authors.forename: Sally
authors.initials: S
authors.lastname: Dixon
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Leesnitzer
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Orband-Miller
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Williams
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Willson
authors.forename: Robert
authors.initials: R
authors.lastname: Xu
authors.forename: William J
authors.initials: WJ
authors.lastname: Zuercher
authors.forename: Fang
authors.initials: F
authors.lastname: Cai
authors.forename: Holly A
authors.initials: HA
authors.lastname: Ingraham
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054339:Steroidogenic Factor 1 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D008024:Ligands; C082631:NR5A2 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D054852:Small Molecule Libraries; D054339:Steroidogenic Factor 1